Trifluoroacetic acid → 4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-1-(2,2-difluoroethyl)-N,N-dimethylpiperazine-2-carboxamide

HRID 921829Notes

Reaction equation

HRID 921829 reaction equation
[Cl:1][C:2]1[C:7]([NH:8][C:9]2[N:14]=[C:13]([N:15]([CH:25]3[CH2:27][CH2:26]3)CC3C=CC(OC)=CC=3)[C:12]3=[N:28][CH:29]=[C:30]([C:31]#[N:32])[N:11]3[N:10]=2)=[CH:6][C:5]([C:33]#[N:34])=[CH:4][C:3]=1[N:35]1[CH2:40][CH2:39][N:38]([CH2:41][CH:42]([F:44])[F:43])[CH:37]([C:45]([N:47]([CH3:49])[CH3:48])=[O:46])[CH2:36]1.C1(OC)C=CC=CC=1.C(O)(C(F)(F)F)=O>ClCCCl>[Cl:1][C:2]1[C:7]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH:25]3[CH2:26][CH2:27]3)[C:12]3=[N:28][CH:29]=[C:30]([C:31]#[N:32])[N:11]3[N:10]=2)=[CH:6][C:5]([C:33]#[N:34])=[CH:4][C:3]=1[N:35]1[CH2:40][CH2:39][N:38]([CH2:41][CH:42]([F:43])[F:44])[CH:37]([C:45]([N:47]([CH3:49])[CH3:48])=[O:46])[CH2:36]1

Participants

5

Reactant 3

HCID 6422Trifluoroacetic acid3×HCID 7519AnisoleHCID 89923142HCID 89923142, compound

Product 1

HCID 899227344-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-1-(2,2-difluoroethyl)-N,N-dimethylpiperazine-2-carboxamideYield 65.3%

Reagents, catalysts & solvents 1

HCID 111,2-DichloroethaneSolvent

Procedure

4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropyl(4-methoxybenzyl)amino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-1-(2,2-difluoroethyl)-N,N-dimethylpiperazine-2-carboxamide (37 mg, 0.054 mmol) was taken up in DCE (0.5 mL) and anisole (0.029 mL, 0.268 mmol) was added, followed by TFA (0.124 mL, 1.608 mmol). The reaction was stirred at room temperature overnight. LCMS indicates mostly SM is present. An additional 30 eq. of TFA was added and the reaction was heated at 50° C. After 4 h, an additional 30 eq. of TFA was added, and the reaction heated for 1.5 h. The solvent was removed in vacuo and the material azeotroped 2× with toluene, then triturated with Et2O to remove anisole. The material was purified by preparative HPLC to provide 4-(2-chloro-5-cyano-3-((7-cyano-4-(cyclopropylamino)imidazo[2,1-f][1,2,4]triazin-2-yl)amino)phenyl)-1-(2,2-difluoroethyl)-N,N-dimethylpiperazine-2-carboxamide (20.1 mg) as a yellow solid.

Workup

  1. temperaturethe reaction was heated at 50° C
  2. waitAfter 4 h
  3. temperaturethe reaction heated for 1.5 h
  4. customThe solvent was removed in vacuo
  5. customthe material azeotroped 2× with toluene
  6. customtriturated with Et2O
  7. customto remove anisole
  8. customThe material was purified by preparative HPLC

Sources & evidence

ORD record
ord-d6b685fbb73540758ab13b1626976335
Source dataset
uspto-grants-2016_03
Patent number
US09273057B2

Reaction notes

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